A NOVEL KINASE CASCADE MEDIATED BY MITOGEN-ACTIVATED PROTEIN-KINASE KINASE-6 AND MKK3

A cDNA encoding a novel member of the mitogen-activated protein kinase kinase (MAPKK) family, MAPKK6, was isolated and found to encode a pro tein of 334 amino acids, with a calculated molecular mass of 37 kDa th at is 79% identical to MKK3. MAPKK6 was shown to phosphorylate and spe cifically activate the p38/MPK2 subgroup of the mitogen-activated prot ein kinase superfamily and could be demonstrated to be phosphorylated and activated in vitro by TAK1, a recently identified MAPKK kinase. MK K3 was also shown to be a good substrate for TAK1 in vitro. Furthermor e, when co-expressed with TAK1 in cells in culture, both MAPKK6 and MK K3 were strongly activated. In addition, co-expression of TAK1 and p38 /MPK2 in cells resulted in activation of p38/MPK2. These results indic ate the existence of a novel kinase cascade consisting of TAK1, MAPKK6 /MKK3, and p38/MPK2.